The present invention relates to novel acylamino cyclopropane derivatives, processes for their preparation, pharmaceutical compositions containing them and their use as modulators of dopamine D3 receptors and for the treatment of anxiety, psychosis, substance abuse, Parkinsons disease, sexual dysfunction, and other central nervous system disorders.
The dopamine D3 receptor (the “D3 receptor”) subtype has been identified (Sokoloff, P. et al., Nature, 1990, 347, 146). The D3 receptor is preferentially expressed in limbic brain regions such as the septal area and amygdala (Landwehrmeyer et al., Mol. Brain Res. (1993), 18 (1–2), 187–92). These regions are thought to be important brain areas for the regulation of cognition, motivation and emotion (Graeff et al., Braz. J. Med. Biol. Res. (1994), 27(10), 2453–6). The unique localization of D3 receptors and their differential recognition of various antipsychotics suggest that such receptors may play a major role in the etiology of schizophrenia.
Moreover, in patients suffering from Parkinson's disease (PD), repeated administration of levodopa, a dopamine precursor, results in progressive resumption of motor performances as well as in development of abnormal involuntary movements, suggesting sensitization to the drug. In a rat model of PD, it was shown that the unexpected appearance of the dopamine D3 receptor in the denervated caudate putamen, an area from which it is normally absent, accounts for the sensitization process: sensitization occurs and declines with the same time course and sensitization is blocked by a preferential D3 receptor antagonist; suggesting that dopamine D3 receptor antagonists may be useful in therapy of PD. Biomed. Health Res. (2000), 26, “Molecular Biology Approach to Parkinson's Disease”, edited by Jenner, P., 49–60.
It has been shown that a dopamine D3 receptor partial agonist reduced the response to cocaine cues in rats suggesting that D3 antagonists may be useful for the development of substance abuse therapies. Pilla et al., 1999, Nature, 440: 371–375. In addition, mice without functional D3 dopamine receptors were examined animal models for anxiety. Physiol. Behav. (1997), 1998, 63(1), 137–141. The authors interpreted their results as indicative of reduced anxiety in mice without D3 receptos, suggesting that D3 dopamine receptor modulators may be useful for treatment of anxiety.
It has also been was shown that a structural congener of 7-OH-DPAT (7-Hydroxy Diisopropyl Amino Tetraline), primarily characterized as a D3 receptor selective ligand, produces a facilitation of male rat ejaculatory behavior, as evidenced by a dose-dependent decrease in the number of intromissions preceding ejaculation and in time to ejaculation, suggesting that dopamine D3 modulators may be useful in treatment of sexual dysfunction, e.g., for treatment of premature ejaculation. Ahlenius et al., Pharmacol., Biochem. Behav. (1995), 51(2/3), 545–7.
It is well accepted that dopamine receptors play an important role in the regulation of cardiovascular and kidney function. Recently, the peripheral actions of the D3 dopamine receptor subtype have also raised considerable interest as well because the dopamine D3 receptor subtype was identified in rat kidney and it has been shown in animal models that the disruption of D3 receptors at the gene level causes hypertension in mice and that D3 modulators effect sodium excretion in the rat kidney and the secretion of renin. Luippold et al., “Dopamine D3 Receptor Activation Modulates Renal Function in Anesthetized Rats”, Naunyn-Schmiedeberg's Arch. Pharmacol. (1998), 358(6), 690–693.
Thus, dopamine D3 receptor modulators may also provide therapeutic potential as diuretics or anti-diuretics, treatment of urinary incontinence and in treatment of various cardiovascular pathological conditions, including hypertension. See, e.g., Asico, et al., J. Clin. Invest., 1998, 102(3), 493–498; Luippold et al., Acta Physiol. Scand., 2000, 168, 219–223.
Compounds of formula (I), which have described below, have been found to exhibit greater affinity for D3 receptor than for the dopamine D2 receptor (“D2 receptor”), and are expected to be useful in the treatment of diorders that can be treated by modulating the D3 receptor, such as psychotic conditions, anxiety, depression, Parkinson's disease, substance abuse, sexual dysfunction, and movement disorders.